Antibacterial medicinal compositions

ABSTRACT

THERAPEUTIC COMPOSITIONS ARE DESCRIBED WHICH COMPRISE A MIXTURE OF (A) A 3-(SUBSTITUTED BENZAMIDO)-4-HYDROXY8-METHYL-7-(3-0-(5-SUBSTITUTED-2 -PYRROLYLCARBONYL)NOVIOSYLOXY)-COUMARIN OR A NONTOXIC PHARMACEUTICALLY ACCEPTABLE CATIONIC SALT THEREOF AND (B) N-METHYLGLUCAMINE. THE COMPOSITIONS CAN BE FORMULATED INTO SUITABLE DOSAGE FORMS FOR ORAL ADMINISTRATION AND, WHEN SO ADMINISTERED, SATISFACTORY BLOOD LEVELS OF THE ACTIVE INGREDIENT ARE ACHIEVED AT RELATIVELY LOW DOSAGES.

United States Patent Office 3,703,580 Patented Nov. 21, 1972 ANTIBACTERIAL MEDICINAL COMPOSITIONS Harold Leon Newmark, Maplewood, N.J., assignor to Holi'mann-La Roche Inc., Nutley, NJ.

No Drawing. Filed Aug. 29, 1969, Ser. No. 854,260 Int. Cl. A6lk 21/00 U.S. Cl. 424-181 5 Claims ABSTRACT OF THE DISCLOSURE BRIEF SUMMARY OF THE INVENTION The present invention provides compositions which contain the known antibacterial 3-(substituted benzamido)- 4-hydroxy 8 methyl-7-[3-0-(5-substituted 2 pyrrolylcarbonyl)-noviosyloxy]coumarins or nontoxic pharmaceutically acceptable cationic salts thereof in admixture with N-methylglucamine. The compositions are produced simply by mixing the N-methylglucamine and the aforesaid coumarins together. Subsequently, the compositions are worked-up by conventional procedures and techniques for oral administration. The compositions can contain various compatible additional medicaments.

The invention serves to provide oral dosage forms from which the antibiotics, known to be active against certain infectious bacteria, are absorbed into the blood stream at higher levels than heretofore possible, even when administered at low dosages.

DETAILED DESCRIPTION OF THE [INVENTION The present invention provides new and useful compositions suitable for oral administration which contain as the active ingredients, compounds selected from the group consisting of those represented by the formula H30 O 0 HaC 0 i moo NH Ar OH \I/ 0 OH (:0

wherein R is either hydrogen or methyl, and Ar is a group represented by the formula in which each of R, R and R represents hydrogen, fiuoro, chloro, bromo, iodo, trifluoromethyl, trichloromethyl, amino, N-lower alkylamino, N,N-di-lower alkylamino, nitro, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, hydroxy, carboxami do, N-lower al kylcarboxamido, N,N-di-lower alkylcarboxamido, carboxy, carb-lower alkoxy, acetoxy, mercapto, thioacetoxy or lower alkylthio; and the nontoxic, pharmaceutically acceptable cationic salts thereof.

While all the known antibacetrial compounds embraced by Formula I are suitable in the compositions of this invention, those which constitute a preferred embodiment are represented by the following formula wherein -R is either hydroxy or halogen and R is either hydrogen, lower alkyl or lower alkenyl; and the nontoxic, pharmaceutically acceptable cationic salts thereof.

The term lower alkyl as used herein means both straight and branched chain aliphatic hydrocarbon radicals having from one to eight carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isbutyl, t-butyl, amyl, hexyl, etc. Where the term lower is used as part of the description of another group, e.g., lower alkoxy, it refers to the alkyl portion of such group which is therefore as described above in connection with lower alkyl" and thus includes such radicals as methoxy, ethoxy, isopropoxy, etc. The term lower alkenyl as used herein means both straight and branched chain unsaturated hydrocarbon radicals of the formula wherein n is a whole integer of 2 to 8, i.e.,

CH2 OH:c (CH3)2, --CH:CH2, etc.

Similarly, the term lower alkynyl as used herein means both straight and branched chain unsaturated hydrocarbon radicals of the formula wherein n is a whole integer of 2 to 8, i.e.,

CH2CECCH3, --CEC-CH(CH3)2, etc.

The compounds utilized as the active ingredients in the compositions of this invention are known and can be prepared by known processes and methods, particularly those disclosed in U.S. Patent No. 3,428,623.

The compositions of the invention are mixtures comprising (a) a compound represented by Formula I or more preferably Formula II, and (b) N-methylglucamine. The compositions may also contain conventional pharmaceutical excipients, adjuvants and/or pharmaceutically compatible medicaments. Suitable pharmaceutically compatible medicaments which may be admixed in the compositions of the present invention are antihistamines, sulfa drugs [e.g., sulfadiazine, sulfabenzamide, sulfacetamide, sulfanilamide, sulfapyridine, sulfathiazole, sulfapyrazine, sulfaguanidine, sulfathalidine, sulfasuxidine, sulfisoxazole, sulfamylon, phthalylsulfacetamide, N'-3,4-dimethylbenzoylsulfanilamide, benzylsulfanilamide and N-2-(2-quinoxalyl)sulfanilamide], stimulants of the central nervous system (e.g., caffeine, amphetamines), analgesics (e.g., aspirin, salicylamide, sodium gentisate, p-acetylaminophenol, phenacetin, codeine), laxatives (e.g., phenolphthalein), sedatives (e.g., barbiturates, bromides), salts of penicillin, phenoxymethylpenicillin and salts thereof, other antibiotic agents (e.g., streptomycin, dihydrostreptomycin, bacitracin, polymixin, tetracycline, erythrornycin, chlortctracycline, oxytetracycline, oleandomycin, chloramphenicol, magnamycin, novobiocin, cycloserine; in some cases such combinations attack a wider range of organisms or show synergistic efficacy or provide decreased toxicity with equal efficacy), vitamins (e.g., vitamins A, A B B B B and members of that family, folic acid and members of that family, vitamins C, D D and E), hormones (e.g., cortisone, hydrocortisone, 9a-fiuorocortisone, 9u-fluorohydrocortisone, prednisone and prednisolone), anabolic agents (e.g., 11,17-dihydroxy- 9a-fluoro 17a methyl-4-and-rosten-3-one; 17a-ethyl-l9- nortestosterone) and antifungal agents (e.g., mycostatin).

In carrying out the invention, the active compounds can be employed in the form of the free acid or in the form of a nontoxic, pharmaceutically acceptable cationic salt of the free acid with a medicinally acceptable base. Thus, suitable for use are salts of the free acid, such as, for example, sodium, potassium, calcium, aluminum and ammonium salts, nontoxic substituted ammonium salts with an amine selected from the group consisting of trialkylamines, procaine, dibenzylamine, N-benzyl-betaphenethylamine, l-ephenamine, N,N'-dibenzylethylenediamine, dehydroabiethylamine, N,N'-bis-dehydroabietylethylenediamine and N-(lower)alkylpiperidines, e.g., N-ethylpiperidine. In the preferred embodiment of the invention, either the free acid or an alkali metal salt thereof, for example, the monosodium salt, is employed. It is to be understood that the previously mentioned salts are merely illustrative of the salts employed in the practice of the invention and such listing is not intended as limitative on the practice of this invention.

The compositions of the invention are readily produced. The preparative method involves simpl mixing the active compound and N-methylglucamine. Generally, the mixing step is carried out without the aid of a solvent. However, if desired, the ingredients can be admixed in a liquid vehicle which is a solvent for both. The quantity of active compound and the quantity of N-methylglucamine which is used in producing the compositions is variable within certain prescribed limits. In general, the compositions of the invention will contain from about 0.5 to about 100 moles of N-methylglucamine per mole of the active compound present. The compositions which are produced in the preferred embodiment of the invention, however, will contain from about 2 to about 25 moles N-methylglucamine for each mole of active compound present.

The compositions of this invention, i.e., the mixture of active compound with N-methylglucamine, are ultimately worked-up to provide pharmaceutical preparations which are suitable for oral administration. These pharmaceutical preparations may be in solid form, for example, tablets, drage'es or capsules. The tablets can be single or multilayer and they may be coated. In the alternative, the preparations may be in liquid form, for example, solutions, emulsions or suspensions. In producing these pharmaceutical preparations, conventional pharmaceutically acceptable adjuvants and excipients, either organic or inorganic in nature, are employed. Such adjuvants and excipients include water, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils, gums, petroleum jellies, glycerol, ethyl alcohol, propylene glycol and other such materials. The methods and techniques, as well as the adjuvants and excipients, which are used in formulating the compositions of the present invention into particular solid oral dosage forms will be readily apparent to those skilled in the art. For example, the compositions with or without appropriate pharmaceutical excipients and adjuvants, can be filled into hard or soft shell capsules. In the alternative, the compositions can be compressed into tablets which can, if desired, be film coated or sugar coated. The manner in which the present compositions are formulated into liquid pharmaceutical preparations, e.g., solutions for oral administration, will similarly be apparent to persons skilled in the art. For example, in producing solutions, the mixture can be dissolved in a pharmaceutically acceptable solvent. In an alternative embodiment of the invention, the active ingredient and N-methylglucamine can be added separately to the pharmaceutical excipients or adjuvants, either liquid or solid, to form, in situ, the desired mixture of medicament and N-methylglucamine.

The quantity of inert pharmaceutical excipients and adjuvants used in producing various dosage forms will vary, depending upon the properties and characteristics of the excipients or adjuvants in use and the nature of the dosage form to be formulated. In general, however, pharmaceutical preparations of the present invention, in unit dosage form, will provide from about 10 mg. to about 400 mg. of medicament. The frequency with which the pharmaceutical preparations of this invention are administered will vary depending upon the level of active medicament present therein and the needs and requirements of the subject to be treated. In general, however, in the case of capsules or tablets containing 50 mg. of medicament, a typical adult dose is one tablet or capsule four times daily or every six hours. In the case of a capsule or tablet containing mg. of medicament, a typical adult dose of such tablet or capsule would be one capsule twice daily or every twelve hours. It should be understood, however, that the dosages enumerated herein are exemplary only and that they are not intended to limit the scope of practice of the present invention. In any particular instance, the dosage can be adjusted to satisfy the needs and requirements of the subject to be treated.

The present invention serves to provide pharmaceutical compositions, in unit dosage form, which contain a compound represented by Formula I as the active ingredient and in its preferred embodiment, those represented by Formula II. The compositions, thus produced, are suitable for use in the oral treatment of microbial infections. When so used, higher blood levels of the active compound will be achieved than heretofore possible at relatively low dosages. The invention, therefore, is of significant importance since it provides means whereby the medicaments can be self-administered by the subject, with the assurance that the active ingredient will be absorbed reliably and consistently into the blood stream.

For a fuller understanding of the nature and objects of this invention, reference may be had to the following illustrative examples.

Example 1 In this example, the following named ingredients, in the quantities indicated, were charged into a suitable container:

Ingredients: Mg. per capsule 3 (3 isopropyl 4 hydroxybenzamido) 4- hydroxy 8 methyl 7 [3 0 (5 methyl- 2 pyrrolylcarbonyl) noviosyloxy] coumarm N-methylglucamine 200 The named ingredients were ground together in a mortar until uniform, following which the mixture was filled into gelatin capsules.

Example 2 In this example, the following named ingredients, in the quantities indicated, were charged into a suitable container:

Ingredients: Mg. per capsule 3 (3 hexyl 4 hydroxybenzamido) 4 hydroxy 8 methyl 7 [3 methyl- 2 -'pyrrolylcarbonyl) noviosyloxy] couma- In this example, the following named ingredients, in the quantities indicated, were charged into a suitable container:

Ingredients:

3 [3 (3 methyl 2 butenyl) 4 hydroxybenzamido] 4 hydroxy 8 methyl -.-7-

[3 0 (5 methyl 2 pyrrolylcarbonyl)- Mg. per capsule 6 Ingredients: Mg. per capsule 3 (4 bromobenzamido) 4 hydroxy 8- 'methyl 7 [3 0 (5 methyl 2 pyrrolylcarbonyl)-noviosyloxy]-coumarin N-methylglucamine 200 The named ingredients were ground togeher in a mortar until uniform, following which the mixture was filled into gelatin capsules.

Example 6 The compositions, produced as described in Examples 1-5 inclusive, were administered orally to dogs. Capsules, 50 mg. each with and without 200 mg. N-methylglucamine, were administered to each of four dogs for each compound and blood level determinations were made at specific intervals. The blood assays were performed by a microbiological cup-plate assay method using Staphylococcus aureus as the test organism. The sensitivity of the assay is 0.08 mcg./ml. in blood, and the precision of the assay is better than 120%. The blood level determinations were made 1, 2, 4, 8, 24 and 48 hours after the oral administration of the composition.

nov1osyloxy]-coumar1n 5 0 The table which follows hereinafter sets forth the re- N-methylglucamine 200 sults of the blood level determination,

TABLE Micrograms per/milliliter of serum Dose, 2 4 8 24 48 Composition mg. 0 hour 1 hour hours hours hours hours hours 3-(3-lsopropyl-4-hydroxybenzamldo)-4-hydroxy-8-rnethyl-7-l3-0- (5-methyl-2-pyrrolylearbonyl)-n0vlosyloxy]-coumarin 0. 24 2. 3 8. 9 5, 0 0, 7 0 2 24 3-(f-lsopg:qyll-hydfofrybgnzagildo)14-h3idro1fy-8-m$yl-7- b-met y '2-pyrr0 y car ony -nov osy oxy -coum n t 1 1 m 200 19 24 18 0. 24 0. 24 3-(ii-hexyl-4-hydroxybenzamldo)-4-hydroxy-8-methyl-7-[3-0-(5-methyl- 2-pyrrolylcarbonyl)-novlosyloxy]-coumarln 10 0- 24 0- 6 0. 5 0. 24 0. 24 0. 24 3-3-hexylfi-hygroxylrrenziimlrlo)4ihydroxyi8-methyl 50 -pyrro y car ony -nov osy oxy eoumar n. Nqnethylglucamine 200 1 6 3 0.24 0. 24 3-[3-(3-methyl-2-butenyl)-4-hydroxybenzamldoH-hydroxy-8-methyl 7-[3-0-(ti-mathyl-2-pyrrolylcarbonyl)-noviosyloxy-coumarln 60 0. 24 0.3 0.5 0. 24 0.24 0, 24 0. 24 3-531 g3-nzgthyi-r2-liuztenyl) iii-hydoxyllafnzariildol]-4-liydroxy-8i;lmethyl- 50 -0- -me y -pyrro y car ony -nov osy oxy -coumar N-methylglueamh e 24 5 3 8 5 0 24 0. 24 3-[3-(3-methyl-Z-butenyl)-4-hydroxybenzamldo1-4-hydrcXy-B-meth 7-[3-0-(5-methyl-2-pyrrolcarbonyl)-novlosyloxy1-coumarin sodium salt -L' 50 0. 6 0. 5 0. 5 0. 5 0. 5 0, 5 5 3-[3-(3 methyl-2-butenyl) -4-hydroxybenzamldo]-4-hydroxy-8-methyl- 7-[l3-0-(5-methyl-2-pyrro1y1carbonyl)-novlosylox umarin sodium 50 sa t N-methylglucamlng 200 5 5 9 3 7 1. 5 0. 5

The named ingredients were ground together in a mortar until uniform, following which the mixture was filled into gelatin capsules.

Example 4 In this example, the following named ingredients, in the quantities indicated, were charged into a suitable container:

The named ingredients were ground together in a mortar until uniform, following which the mixture was filled into gelatin capsules.

Example 5 In this example, the following named ingredients, in the quantities indicated, were charged into a suitable container:

The foregoing results demonstrate that the oral administration of representative compounds represented by Formula I, in admixture with N-methylglucamine, enhance their absorption into the blood stream and the levels in the blood stream are maintained for a longer period of time than without N-methylglucamine.

L I claim:

1. A pharmaceutical composition in unit dosage form possessing antibacterial activity upon oral administration comprising (a) 3-[3-(3-methyl 2 butenyl)-4-hydroxybenzamido]-4-hydroxy-8-methy1- 7 [3 O (S-methyl-Z- pyrrolylcarbonyl)-noviosyloxy]-coumarin sodium salt, and (b) N-methylglucamine, there being present in said composition from about 4 moles of N-methylglucamine per mole of said ingredient (a).

2. A pharmaceutical composition in unit dosage form possessing antibacterial activity upon oral administration comprising (a) 3-[3-(3-methyl-2-butenyl)-4-hydroxybenzamido] 4 hydroxy 8 methyl-7-[3-O-(5-methyl-2-pyrrolylcarbonyl)-noviosyloxy]-coumarin and (b) N-methylglucamine, there being present in said composition from 4 moles of N-methylglucamine per mole of said ingredient 3. A pharmaceutical composition in unit dosage form possessing antibacterial activity upon oral administration comprising (a) 3-(3-hexy1-4-hydroxybenzamido)-4-hydroxy 8 methyl-7-[3-O-(S-methyl-Z-pyrrolylcarbonyl)- noviosy10xy1-coumarin and (b) N-methylglucamine, there being present in said composition from 4 moles of N-methylglucamine per mole of said ingredient (a).

4. A pharmaceutical composition in unit dosage form possessing antibacterial activity upon oral administration comprising (a) 3-(3-isopropyl-4-hydroxybenzamido)-4 hydroxy 8 methyl-7-[3-O-(5-methyl-2-pyrrolylcarbonyl)-noviosyloxy]-coumarin, and (b) N-inethylglucamine, there being present in said composition from 4 moles of N-methylglucamine per mole of said ingredient (a).

5. A pharmaceutical composition in unit dosage form possessing antibacterial activity upon oral administration comprising (a) 3-(4-bromobenzamido) 4 hydroxy-8- References Cited UNITED STATES PATENTS 2/1969 Keiletal 424181 OTHER REFERENCES Derwent Farmdoc #26344, S.A. 66/5644, published Feb. 27, 1967, pp. 457-468.

JEROME D. GOLDBERG, Primary Examiner US. Cl. X.R. 42418l, 

